| dc.description.abstract | The thesis entitled "Synthetic Studies in Terpenoids" consists of six chapters.
In Chapter 1, the first total synthesis of 8, a norsesquiterpene occurring in the plant Isocoma wrightii, is described. Succinoylation of 4-t-butyl-o-xylene, under Friedel-Crafts conditions, gave a mixture of keto acids 1 and 3, which were separated as their methyl esters 2 and 4 respectively. Ester 5, obtained from 2 by de-t-butylation, gave on modified Clemmensen reduction the arylbutanoate 6. Grignard reaction of 6 with MeMgI, followed by cyclodehydration of the resulting tertiary alcohol, produced the natural product 8.
Chapter 2 deals with the conversion of the norsesquiterpene 8 to chrysolic acid (13), a diterpenoid isolated from the desert plant Chrysothamnus paniculatus. Tetralin 8 on chloromethylation gave 9. Condensation of 9 with ethyl sodioacetoacetate gave the keto ester 10, which on decarbethoxylation afforded 11. Modified Reformatsky reaction of 11 with t-butyl bromoacetate, followed by thermal treatment of the product (12), furnished chrysolic acid (13).
Chapter 3 describes the synthesis of two isomeric sesquiterpenic metabolites (21 and 25), isolated from tobacco leaves inoculated with tobacco mosaic virus (TMV). Stobbe condensation of 2,3-dimethylbenzaldehyde (15) (prepared from o-xylene by a novel route via the t-butyl compound 14) with diethyl succinate gave the half-ester 16. Simultaneous reduction and hydrolysis of 16 gave the diacid 17. Cyclodehydration to the tetralone acid 18, followed by its Clemmensen reduction, gave 19. Grignard reaction of its methyl ester 20 with MeMgI afforded the metabolite 21. In the synthesis of the second metabolite 25, tetralone 22, the cyclodehydration product of 7 derived from 6 already referred to, served as the key synthon. Carbethoxylation of 22 produced the keto ester 23. Modified Clemmensen reduction of 23, followed by the action of MeMgI on the resulting ester 24, furnished 25.
In Chapter 4 is described a simple benzoannulation procedure involving cyclization of 2,4-dienoic acids (28, R¹ = H) and its application in the synthesis of terpenoids (-)-(R)-curcuphenol acetate (33), (-)-(1R,4S)-8-hydroxy- and -8-methoxycalamanenes (37 and 38) and (+)-(R)-dihydropyrocurzerenone (44). The 2,4-dienoic acids 28 (R¹ = H) underwent cyclization, in the presence of sodium acetate in acetic anhydride under reflux, to give the phenolic acetates 29. The 2,4-dienoic acids 28 (R¹ = H) were prepared by the basic hydrolysis of the corresponding esters 28 (R¹ = Me), which in turn were obtained by the Wittig-Horner reaction of the carbonyl compounds 26 (R¹,R² = H or alkyl), with the phosphonate 27 (R³ = H or Me). The generality of this benzoannulation procedure was established by a variety of successful transformations, viz., acetaldehyde to phenyl acetate; propionaldehyde to o-cresyl acetate; acetone to both m-cresyl acetate (29, R¹ = H; R² = Me) and 3,5-dimethylphenyl acetate (29, R¹ = H; R² = R³ = Me); and cyclohexanone to 30. Further examples are the conversion of isovaleraldehyde to the monoterpene thymol acetate (31), (+)-(R)-citronellal (32) to the sesquiterpenic (-)-(R)-curcuphenol acetate (33), and menthone (34), prepared from (+)-(R)-pulegone (35), to the acetates 36 and 37. Acetate 36 on hydrolysis gave (-)-(1R,4S)-8-hydroxycalamenene (37) and methylation of 37 gave (-)-(1R,4S)-8-methoxycalamenene (38). Both 37 and 38 are enantiomers of naturally occurring 8?-hydroxy- and 8-methoxycalamenenes (constituents of the seaweed Dysoxylum acutangulum and the horny coral Subergorgia hicksoni, respectively). (+)-(R)-Pulegone (35) on Wittig-Horner condensation with triethyl phosphonoacetate, followed by basic hydrolysis of the product, gave a mixture of 2,4- and 3,5-dienoic acids. Treatment of the mixture with sodium acetate-acetic anhydride under reflux led to cyclization to give the bicyclic acetate 41 in high yield. The tetrahydronaphthol secured from 41 was converted to the acetonate which on cyclodehydration gave (+)-(R)-dihydropyrocurzerenone (44, the enantiomer of the natural product isolated from the roots of Chloranthus serratus), along with a small amount of the linear furan 45.
Chapter 5 discusses the iodoxybenzene oxidation of 1-naphthols and its application in the synthesis of natural products emmotin H (47) and mansonone A (48). Oxidation of unsubstituted, 3-methyl-, 7-methyl-, 6-methoxy-, 7-methoxy- and 8-methoxy-1-naphthols, using iodoxybenzene in aqueous acetonitrile, gave the corresponding 1,2- and 1,4-naphthoquinones. Similar oxidation of naphthol 46, prepared according to a published procedure, gave emmotin H (47, one of the emmotins reported from the trunk wood of Emmotum nitens) as the sole product. Iodoxybenzene oxidation of (-)-(1R,4S)-8-hydroxycalamenene (37) gave mansonone A (48, an allergen from the heartwood of Mansonia altissima) and the corresponding p-quinone 49.
In Chapter 6 is presented the selective benzylic oxidation of 4-acyltoluenes, using benzyltriethylammonium permanganate (BTAP), which led to the synthesis of sydonic acid (53, a sesquiterpenic metabolite from the culture filtrates of Aspergillus sydowi) and an ester 55, an intermediate in the synthesis of pyrenochaetic acid A (57, a phytotoxin from the culture filtrates of Pyrenochaeta terrestris, the causal fungus of onion pink root disease). Oxidation of the acetoxy ketone 52 using BTAP in aqueous acetic acid gave the phenolic keto acid 54. Treatment of 52 with excess of isohexylmagnesium bromide gave sydonic acid. Oxidation of 56 by BTAP, followed by methylation of the resulting mixture of acids, gave the methoxy methyl keto esters 58 and methyl 4,6-dimethyl-2-methoxybenzoate. Oxidation of 56 by BTAP gave an inseparable mixture of acids 59, the former being the one required for further elaboration to hydroxysydonic acid (54). | |
